Evaluation and Treatment of Osteoporosis

Evaluation and Treatment of

Osteoporosis

Ingeborg Sacksen MD Bellingham Arthritis and Rheumatology Center

Clinical Associate Professor

University of Washington

1

SACKSEN

Audience Response Question

SACKSEN

Audience Response Question

*Consensus Development Conference: Diagnosis, Prophylaxis, and

Treatment of Osteoporosis. Am J Med. 1991;90:107. *Images used with permission of David Dempster, PhD. Copyright 2001

“

A systemic skeletal disease

characterized by low bone

mass and micro-architectural

deterioration of bone tissue

with a consequent increase

in bone fragility and

susceptibility to fracture.*

4

What is Osteoporosis?

Normal Bone*

Osteoporotic Bone*

“Porous Bone”

Bone density maximum at age 30 and

its all down hill after that!

Gender and ethnic factor important in maximum bone density and therefore density as a person ages

Susan Ott, MD

Osteoporosis is Common

• Most common bone disease

10 million Americans have osteoporosis and

33.6 million have low bone density at the hip.

Over 200 million worldwide

• Approximately 50% of Caucasian women and

20% of men will experience an osteoporotic

fracture

6

National Osteoporosis Foundation Clinician’s Guide 2008

www.iofbonehealth.org/health-professionals/about-osteoporosis/epidemiology

1. Riggs BL and Melton LJ III, Bone. 1995;17(suppl.):505S-511S.

2. Heart and Stroke Facts: 1996 Statistical Supplement, American Heart Assoc.

3. Cancer Facts & Figures-1996, American Cancer Society.

Osteoporotic Fractures Are More Common

Than Sequelae of Other Chronic Diseases

1,500,000

0

500,000

1,000,000

1,500,000

2,000,000

Osteoporotic

fractures (1)

* annual incidence all ages ** annual estimate women 29+ † annual estimate women 30+

‡ 1996 new cases, women all ages

*

513,000

Heart attack (2)

**

228,000

Stroke (2)

†

184,300

Breast cancer (3)

‡ 750,000 vertebral

250,000 other sites

250,000 forearm

250,000 hip

An

nu

al

inc

ide

nc

e o

f c

om

mo

n d

ise

as

es

Hip Fractures have Serious

Complications

• Up to 24-30% excess mortality with 1 year

• Nearly 65,000 women die from complications

of hip fracture each year

• 50% of hip fractures survivors are

permanently incapacitated

• 20% of hip fractue survivors require long term

nursing home care

8

9

Common Secondary Causes • Nutritional

Vitamin D deficiency

• Diseases

COPD

Rheumatoid arthritis

Crohn’s

Malabsorption (Celiac disease, gastric bypass, etc)

• Endocrine

Hypogonadism

• Medications

Glucocorticoids

Anticonvulsants

Aromatase inhibitors or GnRH agonists

Other: SSRIs, PPIs, TZDs?

10

What Testing Should be Done? ASBMR Recommendations

Basic: CBC, chemistry panel, TSH, 25(OH)D, 24

hour urine calcium/creatinine.

Additional: E2, LH, FSH, prolactin, PTH, 1,25-

OHD, 24 hour urine free cortisol,

Iron/TIBC/ferritin, celiac testing, SPEP/UPEP,

ESR/CRP, bone turnover markers, transiliac bone

biopsy (if low trauma fracture and negative

evaluation).

11 Cohen Adi, Shane E. Primer ASBMR 2009;289-293

Indications for DXA • NOF guidelines 2008

All women ≥ 65, men ≥ 70 regardless of clinical risk factors

Younger postmenopausal women and men 50-69 with clinical risk

factors (specific risk factors listed)

Women in the perimenopausal transition if there is a specific risk

factor associated with increased fracture risk

Anyone being treated for osteoporosis, to monitor treatment effect

• USPTF recommendations for screening 2011 All women ≥ 65

Younger postmenopausal women whose fracture risk is equal to an

average 65 y/o without risk factors

No recommendation for men “balance of evidence is insufficient to

assess the balance of benefits and harms of the service”

12

National Osteoporosis Foundation Clinicians Guide 2008 www.NOF.org

www.uspreventiveservicestaskforce.org/uspstf10/osteoporosis/osteors.htm

13

WHO Classification of

Postmenopausal Osteoporosis

T- score

Normal Equal to -1.0 or higher

Low Bone Mass

(Osteopenia) Between -1.0 and -2.5

Osteoporosis Equal to -2.5 or lower

Severe Osteoporosis Equal to -2.5 or lower with fracture

World Health Organization. Technical Report Series 843

WHO, Geneva.1994.

T-score Compares With Young

Adult; Z-score with Age-Matched

14

T-score = Patients BMD- Young Normal Mean BMD

SD of Young Normal

Z-score = Patients BMD- Age Matched Mean BMD

SD of Age Matched

Using T and Z-scores

• T-scores

Used for diagnosis

Only applicable to postmenopausal women or

men over 50

• Z-scores

Used to compare to age-matched controls i.e.

to determine if BMD is what you would expect

at that age

Appropriate for children and healthy adults

under the age of 50

15

Do NOT Use T-scores in:

• Premenopausal Women

• Men Under Age 50

• Children

16

T-score use is inappropriate in these populations as a low value would imply increased fracture risk

Even with low BMD, young healthy people are at low fracture risk (perhaps because they do not have the microarchitectural deterioration that occurs with age

and menopause)

When Should Follow-up DXA

be Performed?

“It depends”

Not more frequently than yearly

Initiation of steroids is an exception (6 months)

ISCD position; measure one year after initiation of Rx to document response (stability or increase)

Medicare has defined monitoring interval as no more frequently than every 23 months

17

Remember that stable BMD on Rx = Success

Problem: Most Women with Hip Fractures

Do Not have Osteoporotic T-scores

Challenge

How can we identify

those with high risk

of fracture who

could benefit from

pharmacological

therapy?

18 Wainwright SA et al. J Clin Endocrinol Metab. 2005;90:2787-2793

FRAXtm: The WHO Fracture Risk Assessment Tool

www.shef.ac.uk/FRAX/

• Assesses 10-year risk of hip

fracture and all osteoporotic

fractures

• Based on risk factors plus or

minus femoral neck BMD

• Fracture probability calculated

from 12 world-wide cohorts

(59,232 individuals, 250K

person-years), validated in 11

independent cohorts

(>1 million person-years)

19

Risk Factors other than Age, Gender

and Race

20 Osteoporos Int. 2007 Aug;18(8):1033-46.

NOF Guidelines Who Should Be Treated?

Fragility fracture hip or spine

T-score ≤ -2.5

T-score -1.0 to -2.5 (osteopenia) and

◊ 10-year hip fracture probability ≥ 3% or a

10-year all major osteoporosis-related

fracture probability of ≥20%

21 www.nof.org

Non-Pharmacologic Therapy

• Nutrition

General

Calcium

Vitamin D

• Exercise

Physical therapy

• Fracture management

Physical Therapy

Surgery

22

23 23

Non-Pharmacological Therapy NOF Recommendations

• Adequate intake of dietary calcium and vitamin D

Calcium: at least 1200 mg/day

Vitamin D: at least 800-1000 IU/day

• Regular weight-bearing and muscle-strengthening

exercise

• Avoidance of smoking and excess alcohol

• Fall prevention

National Osteoporosis Foundation Clinicians Guide 2008

Vitamin D Deficiency(<20ng/ml)

Common and Present in Fracture Patients

• Children

52% blacks and hispanic

48% white girls at the end of the winter in Maine

• Young Adults

32% of medical students and residents in Boston

• Adults >50 years

27% of men, 35% of women

• Fracture Patients:

Hospitalized patients with fragility fracture

◊ 81%<20ng/ml

Women with Hip Fracture

◊ 70%<12ng/ml

24

Musculoskeletal Consequences of

Vitamin D Deficiency

• Impaired calcium absorption ( <20ng/ml)

Increased bone resorption

Increased PTH

Increased rate of bone loss

• Osteomalacia(<12ng/ml)

• Muscle weakness, poor balance and falls

25

Physical Therapy Basics for

Osteoporosis • Discourage

Heavy lifting Back flexion

• Encourage Fall prevention Balance exercises Weight bearing exercise eg walking Back extension exercises

26

Assess Fall Risk

• ASK: Have you fallen in the last year?

• EVALUATE:

Muscle strength

◊ Sit-to-stand without the use of arms

Balance

◊ Heel-to-toe walking

◊ Stand on one foot (begin with holding your

hand or counter)

27

28

Prevention of Falls

• Correct visual and

hearing impairment

• Optimize medications

• Bathroom grab-bars

and nonskid mats

• Avoid throw-rugs and

slippery mats

• Keep electric and

telephone cords

away

• Reduce clutter from walking areas

• Nightlight in bedroom and bathroom

• Handrails on steps and stairs

• Walking aids, if needed

• Exercise for strength and balance (T’ai Chi)

Extension Exercises

29 Reproduced with permission, National Osteoporosis Foundation

Avoiding Flexion and

Managing ADL’s

30 Reproduced with permission, National Osteoporosis Foundation

Use of Back Braces

• Acute fracture Rigid braces used after back surgery are difficult

for patients with osteoporosis to tolerate

Thoracolumbar corsets can decrease pain and increase mobility

Discontinue when acute pain subsides to avoid muscle atrophy

• Chronic back pain Posture training support

Promotes extension

31 Sinaki Osteoporos Int 14:773-779,2003

1 to 3 # weights in posterior pouch

What Would You Recommend?

32

Pharmacologic Therapy

• Antiresorptive

Block osteoclastic bone resorption

• Anabolic

Promote osteoblastic bone formation

33

What is Bone?

• Bone matrix

90% collagen

10% other proteins( osteocalcin, osteonectin,

osteopontin)

• Bone mineral

Hydroxyapatite(calcium and phosphorus)

• Bone cells

Osteoclasts, osteoblasts, osteocytes

34

Bone is Living Tissue that Models

and Remodels

• Modeling

Change in size and shape of bone during

growth in response to physical demands

• Remodeling

Replacement of old bone with new bone in

response to stress damage, microfractures,

and other factors

Important for bone repair and for maintaining

metabolic balance (most remodeling ocurs in

response to metabolic needs)

35

Premenopause: Balanced Bone

Formation and Bone Resorption

36

Resting

Lining cells

Activation

Osteoblasts produce osteoid

Osteoid

mineralized

Reversal

Apoptotic osteoclasts

Active osteoblasts

Formation

Muitinucleated osteoclasts

Sealed resorption cavity

Medications Work at Different

Points of the Remodeling Cycle

37

Resting

Lining cells

Activation

Osteoclasts

Reversal

Formation

Osteoblasts

DMAB

BP’s

PTH

Antiresorptive vs Anabolic Therapy

38

Antiresorptive: fills in resorptive cavity, increases mineralization

Anabolic: produces osteoid, increases connectivity

Osteoporotic Bone: resorptive cavities, loss of connectivity

How do Antiresorptive Agents

Improve Bone Strength?

• Prevent bone loss

• Prevent microarchitectural deterioration

• Decrease stress risers

• Promote mineralization

39

Pharmacologic Therapy

• Antiresorptive

Estrogen

Calcitonin

Raloxifene

Bisphosphonates

Denosumab

40

Osteoporosis is Treatable Evidence that hip fractures are preventable:

• Calcium/Vitamin D1 (France) 43%

• Estrogen2

34% • Alendronate

3 51%

• Risedronate4

39% • Zoledronate5 41% • Denosumab6 40%

41

1 Chapuy NEJM 327:1637, 1992 4 McClung NEJM 344:333, 2001

2 WHI JAMA 288:321,2002 5 Black NEJM 356:1809, 2007

3 Black Lancet 348:1535,1996 6 Cummings NEJM 361:756-765, 2009

NOTE: there are no head-to-head fracture studies so this

data cannot be used to compare treatment efficacy

Estrogen

• BMD: preserves/increases BMD

• Fractures: reduces spine, hip, and forearm fractures by 35%, 33% and 29%

• Extraskeletal considerations Relieves symptoms of estrogen deficiency

Increases risk of breast cancer, VTE, coronary disease, stroke

Endometrial cancer risk in unprotected uterus

Reduces risk of colon cancer

42 Cauley JA, et al. JAMA 2003;290:1729

Nasal Calcitonin Reduces Spine Fractures PROOF Trial: Prevent Recurrence of Osteoporotic Fractures

43

5-year study of 1255 women, average age 68,

with 1-5 prevalent vertebral fractures

Chesnut CH III, et al. Am J Med. 2000;109:267

0

5

10

15

20

25

30

35

Placebo 100 IU 200 IU 400 IU

% S

ub

jects

wit

h N

ew

Vert

eb

ral

Fra

ctu

res

No significant reduction in non-vertebral

fractures or hip fractures

No change in BMD from placebo

36%

P<0.05

Raloxifene

• SERM (selective estrogen receptor modulator) also

known as EAA (estrogen agonist/antagonist)

• BMD: increases at spine and hip

• Fractures: reduces risk of vertebral fractures 30-50%,

no proven benefit for hip or nonvertebral fractures

• Extraskeletal:

reduces risk of breast cancer (approved for

prevention of breast cancer)

does not reduce hot flashes

AE’s: VTE risk, leg cramps

44 Ettinger B, et al. JAMA. 1999;282:637.

Bisphosphonates

• Alendronate: po daily or weekly

• Risedronate: po daily, weekly or monthly

• Ibandronate: po monthly or IV q 3 months

• Zoledronic acid: yearly IV

45

Bisphosphonate

Characteristics • Poorly absorbed • Not metabolized ~ 50% excreted by kidney ~ 50% binds to bone

• High affinity to bone – Binds preferentially at resorptive

surfaces Induces osteoclast dysfunction

• Long skeletal half-life, can recycle

46

Fracture Risk Reduction with

Bisphosphonates in RCTs

• Pivotal fracture trials

Alendronate: FIT 1, FIT 2

Risedronate: VERT, HIP

Ibandronate: BONE

Zoledronic acid: HORIZON

• Results

Spine fractures reduced ~50% in all

Hip fractures reduced ~40% with alendronate,

risedronate and zoledronic acid

47

Bisphosphonate Safety

• Possible GI intolerance with oral agents • Not recommended for GFR < 30-35 ml/min

• Acute phase reaction with IV • Hypocalcemia • Chronic muscle/joint pain? • Oversuppression of bone turnover? • Osteonecrosis of the jaw (ONJ)? • Atypical femoral fractures?

48

Atypical Femur Fractures

• Key characteristics:

- fractures of femoral diaphysis or in

subtrochanteric region

- transverse rather than spiral

- may begin with stress reaction or

stress fracture of lateral femoral

cortex which may be bilateral

- prodromal pain in thigh or groin is

common

- often on other drugs, especially

steroids or estrogen

49

1. Goh S-K, et al. J Bone Joint Surg Br. 2007;89:349-353

2. Imai K, et al. J Bone Miner Metab. 2007;25:333-336

3. Neviaser AS, et al. J Orthop Trauma. 2008;22:346-350

4. Odvina C, et al. J Clin Endo Metab. 2005;90:1294-1301

5. Black DM, et al. N Engl J Med. 2010;362:1761-1771; Epub 2010 Mar 24

6. Shane E, et al. ASBMR Atypical Femoral Fractures Task Force Report. J Bone Miner Res. 2010;25:2267-2294

Denosumab

• Antiresorptive, fully human monoclonal antibody, binds and inhibits RANKL (RANKL triggers activation of osteoclasts)


• Fracture: decreases spine, hip and nonvertebral fracture by 68%, 40%, 20%

• Injection SQ every 6 months

50 Cummings N Engl J Med 2009; 361[8]:756-765

Schematic representation of the basic

multicellular unit of the bone remodelling cycle

Nicholls J J et al. J Endocrinol 2012;213:209-221 © 2012 Society for Endocrinology

52

53

Denosumab Safety

• Hypocalcemia (2% of cases)

• Cellulitis (serious in 0.4%)

• Eczema (10%)

• Osteonecrosis of the jaw (2% in higher dose)

• Back pain (35%), extremity pain (12%), bone

pain (4%)

• Atypical fractures ( Not reported – yet)

• Theoretical Risk - increased infection?

54

Teriparatide: rhPTH(1-34)

• Class: anabolic, hormone


• Bone turnover markers: increased (different from anti-resorptives, which decrease bone turnover markers)

• Fractures: decreases spine and nonvertebral fractures by 65% and 53%, no proven benefit for hip in RCT

• Extra-skeletal considerations:

Osteosarcoma in rats, daily subcutaneous injection, refrigeration, hypercalcemia, leg cramps, dizziness, high cost, limit of 2 years of therapy

55 C Neer RM, et al. N Engl J Med. 2001;344:1434.

Black Box Warning

• In male and female rats, teriparatide caused an increase in the

incidence of osteosarcoma (a malignant bone tumor) that was

dependent on dose and treatment duration. The effect was

observed at systemic exposures to teriparatide ranging from 3 to

60 times the exposure in humans given a 20-mcg dose.

Because of the uncertain relevance of the rat osteosarcoma

finding to humans, teriparatide should be prescribed only to

patients for whom the potential benefits are considered to

outweigh the potential risk. Teriparatide should not be

prescribed for patients who are at increased baseline risk for

osteosarcoma (including those with Paget's disease of bone or

unexplained elevations of alkaline phosphatase, open

epiphyses, or prior external beam or implant radiation therapy

involving the skeleton)

56

Contraindications

• Children and adolescents

• Patients who have had bone cancer

• Patients who have had radiation therapy

• Patients with Paget's disease

• Patients with hypercalcemia or

hyperparathyroidism

• Women who are pregnant or nursing

• Patients with gout or high uric acid

57

Side effects

• Nausea in 8% (similar to placebo)

• Headache in 8%

• Dizziness in 9%

• Leg cramps in 3%

• Hypercalcemia in 11% (usually mild)

• Uric acid increased by 13%

58

Summary: BMD Response

59

Medication Spine Hip

Estrogen

Alendronate

Risedronate

Ibandronate

Zoledronic acid

Calcitonin ~ ~

Raloxifene

Denosumab

Teriparatide

Summary:

Fracture Risk Reduction (PMO)

60

Medication Spine Hip Nonvertebral

Estrogen

Alendronate

Risedronate

Ibandronate

Zoledronic acid

Calcitonin

Raloxifene

Denosumab

Teriparatide

FDA-Approved Medications

61

Drug PMO GIO Men

Prevention Treatment Prevention Treatment

Estrogen

Calcitonin

Alendronate

Risedronate

Ibandronate

Zoledronic

acid

Raloxifene

Denosumab

Teriparatide

We now have multiple choices

for prevention and treatment

of osteoporosis

How do we choose appropriate therapy

for an individual patient?

Guidelines for Clinical Practice for

the Diagnosis and Treatment of


What drugs can be used to treat osteoporosis?

◊ 1st line: ALN, RIS, ZOL, DMAB

◊ 2nd line: IBN, RAL

◊ Other:

• Calcitonin: last line of therapy

• Teriparatide: for patients with very high

fracture risk

• Advise against the use of combination

therapy

63

Watts et al Endoc Pract 2010;16(6):1016-9




How is treatment monitored?

◊ Baseline DXA spine or total hip, repeat every 1-

2 years until stable

◊ Follow-up scans should be in the same facility,

with the same machine, and, if possible, with

the same technician

64

What is successful treatment?

◊ BMD stable or increasing, no fractures

◊ For antiresorptive agents, bone turnover

markers at or below the median value for

premenopausal women

◊ One fracture not necessarily evidence of failure Watts et al Endoc Pract 16(6):1016-9, 2010




How long should patients be treated?

◊ For bisphosphonates, if osteoporosis is mild,

consider a “drug holiday” after 4 to 5 years of

stability

◊ If fracture risk is high, consider a drug holiday

of 1 to 2 years after 10 years of treatment

◊ Follow BMD and bone turnover markers during

a drug holiday period and reinitiate therapy if

bone density declines substantially, bone

turnover markers increase, or a fracture occurs

65 Watts et al Endoc Pract 16(6):1016-9, 2010

Summary of Pharmacologic Rx

• Multiple medications now available for prevention and

treatment of osteoporosis

All have been shown to decrease spine fracture. Effect on

non-vertebral and hip fractures variable

All current medications except teriparatide are antiresorptive

– block action of osteoclasts

Teriparatide is the only current anabolic – increases activity

of osteoblasts

• Bone resorption and bone formation are coupled

• Choosing appropriate therapy for an individual patient

requires consideration of risk/benefit ratio

• Increasing knowledge of bone biology will lead to

additional therapies in the future

66

67

Evolving Therapies

• Promising future breakthroughs

Cathepsin K

Integrins

Sclerostin

Nitrogylcerin

• Medications that are probably effective

Thiazides

Strontium ranelate

68

Evolving Therapies

• Possibly effective drugs

Bicarbonate, Vitamin K

• Conflicting data

Statins, Growth Hormone, Vitamin D

metabolites, Magnesium

• Not effective

Fluoride, Progesterone, Phytoestrogens,

Boron

69

Sclerosteosis

• Sutosomal recessive disease with thick bones,

entrapment of cranial nerves leading to deafness and

facial nerve palsy, increased intracranial pressure,

and frequently syndactyly.

• Most patients are from South Africa and are

homozygotic for a specific mutation in the SOST

gene, which is mapped to 17q12-21.

• None of their 63 patients have ever had a fractured

bone.

• Heterozygous gene carriers are resistant to fractures.

• Do not have degenerative osteoarthropathy.

70

71

SOST and Sclerostin

• SOST is expressed mainly in osteocytes. These cells

form a network which senses mechanical strain.

Osteocytes can alter the secretion of sclerostin to

regulate bone formation.

• Sclerostin inhibits bone formation and enhances

apoptosis of osteoblasts.

• Li X. Targeted deletion of the sclerostin gene in mice

results in increased bone formation and bone

strength. J Bone Min Res 2008:23:860

72

Romosozumab

An Anti-Sclerostin Antibody

73

Romosozumab

An Anti-Sclerostin Antibody

74

QUESTIONS??????

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Documents

Evaluation and Treatment of Osteoporosis